Summary auto-generated
This study investigated the molecular basis of genetic resistance to Murray Valley encephalitis (MVE) virus in mice controlled by the Flv locus on chromosome 5. Researchers analyzed viral RNA species in brains of susceptible C3H/HeJ and resistant C3H/RV mice after intracerebral infection with MVE virus. Using Northern blot analysis, they detected three major viral RNA forms—replicative intermediate (RI), replicative form (RF), and virion RNA (vRNA)—in both mouse strains, plus a novel 0.6 kb subgenomic RNA. Contrary to the prevailing hypothesis, they found no evidence for accumulation of truncated viral RNAs characteristic of defective interfering particles in resistant mice. However, quantitative analysis revealed that resistant mice produced significantly less total single-stranded viral RNA than susceptible mice, with notably greater accumulation of double-stranded RF RNA. The ratio of infectious virus to viral RNA was significantly higher in susceptible mice, suggesting impaired viral packaging or replicon maturation in resistant mice. These findings indicate the Flvr resistance allele interferes with discrete steps in flavivirus replication, though the precise mechanism remains undetermined.
Key findings
- No evidence for accumulation of truncated viral RNAs or defective interfering particles in resistant mice, contradicting prior hypotheses about resistance mechanisms
- Resistant mice accumulated significantly more double-stranded replicative form (RF) RNA relative to single-stranded virion RNA compared to susceptible mice
- Resistant mice produced substantially lower total single-stranded viral RNA levels despite similar early viral titers, indicating interference with a late replication step
- A previously undescribed 0.6 kb subgenomic RNA was detected in both mouse strains but appeared unrelated to resistance
- The Flvr resistance allele appears to impair viral packaging or virion maturation rather than preventing early virus replication
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Abstract
Natural resistance to flaviviruses in mice is controlled by a single genetic locus, FIv, on chromosome 5. Although the mechanism of this resistance is not fully understood, it is believed to operate at the level of virus replication rather than the immune response. It has been hypothesized that enhanced production of viral defective interfering (DI) particles is responsible for a substantial reduction in the titres of infectious virus in resistant mice. However, this has never been established at the molecular level since such particles have not been isolated and characterized. We have studied the products of virus replication in the brains of flavivirus-susceptible C3H/HeJ (Flv(s)) and -resistant congenic C3H/RV (Flv(r)) mice after an intracerebral challenge (i.c.) with Murray Valley encephalitis (MVE) virus and have found no evidence for the accumulation of truncated viral RNA in the brains of resistant mice. All three major viral RNA species, the replicative intermediate (RI), replicative form (RF) and virion RNA (vRNA) together with a subgenomic RNA species of 0.6 kb, which has not been previously described, were present in the brains of both mouse strains. However, the viral RF and RI RNA forms preferentially accumulated in the brains of resistant mice. Thus, we confirm that the resistance allele Flv(r) interferes with discrete steps in flavivirus replication, although the precise mechanism remains to be determined.